# NM_013247.5(HTRA2):c.1316_1320del (p.Val439fs)

https://sugi.bio/variant/htra2-p-val439fs

## Summary

**HTRA2 p.Val439fs (c.1316_1320del)** is classified **Pathogenic** in HTRA2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-12-17). No gnomAD frequency available for this variant; Associated with 3-methylglutaconic aciduria type 8.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1057519080 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the HTRA2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to 3-methylglutaconic aciduria type 8.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Neonatal |
| Diagnostic panels | HTRA2 is a diagnostic-grade gene on 15 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022050/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HTRA2](https://sugi.bio/atlas/gene/HTRA2/) |
| Protein change (HGVS p.) | p.Val439fs |
| Coding change (HGVS c.) | c.1316_1320del |
| MANE Select transcript | [NM_013247](https://www.ncbi.nlm.nih.gov/nuccore/NM_013247) |
| dbSNP | [rs1057519080](https://www.ncbi.nlm.nih.gov/snp/rs1057519080/) |
| Variant type | Deletion |
| Location | chr2:74532920-74532924 (GRCh38) |
| ClinVar | [VCV372210](https://www.ncbi.nlm.nih.gov/clinvar/variation/372210/) |

**All HGVS expressions:** `NC_000002.11:g.74760051_74760055del`, `NC_000002.12:g.74532924_74532928del`, `NG_012163.1:g.8520_8524del`, `NG_033037.1:g.1924_1928del`, `NG_033047.1:g.26012_26016del`, `NM_001289164.3:c.*682_*686del`, `NM_001289165.2:c.*682_*686del`, `NM_001321727.1:c.1250_1254del`, `NM_001321728.1:c.1220_1224del`, `NM_013247.4:c.1316_1320delTGCAG`, `NM_013247.5:c.1316_1320del`, `NM_032603.5:c.*682_*686del`, `NM_145074.2:c.1025_1029del`, `NR_135769.1:n.1958_1962del`, `NR_135770.1:n.1386_1390del`, `NR_135771.1:n.1370_1374del`, `NR_135772.1:n.1390_1394del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.544, GERP 1.6, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.778, pLI 0.00020521. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (8 of 8)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**HTRA2** population constraint: LOEUF 0.778, pLI 0.00020521, missense-Z 2.3681. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **3-methylglutaconic aciduria type 8** — Definitive (AR)

## Protein context {#protein}

Residue **439** lies in the pdz domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 74.83, 51% of residues very-high.

**13 experimental structure(s)** (PDB): [1LCY](https://www.rcsb.org/structure/1LCY), [2PZD](https://www.rcsb.org/structure/2PZD), [5FHT](https://www.rcsb.org/structure/5FHT), [5M3N](https://www.rcsb.org/structure/5M3N), [5M3O](https://www.rcsb.org/structure/5M3O), [5TNY](https://www.rcsb.org/structure/5TNY) — incl. mutant structure 5FHT.

## What this gene does {#gene-function}

*Describes the biological roles of HTRA2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** HTRA2's established molecular role includes serine-type endopeptidase activity. p.Val439fs falls in the pdz domain.


### Pathways affected {#pathways}

HTRA2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |
| [Mitochondrial unfolded protein response (UPRmt)](https://reactome.org/content/detail/R-HSA-9841251) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** serine-type endopeptidase activity, peptidase activity, serine-type peptidase activity, protein serine/threonine kinase inhibitor activity, identical protein binding, ubiquitin ligase inhibitor activity.

**Biological process:** proteolysis, mitochondrion organization, intrinsic apoptotic signaling pathway in response to DNA damage, protein catabolic process, cellular response to oxidative stress, cellular response to heat.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2016-12-17.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2016-12-17 |

## Associated conditions {#conditions}

[3-methylglutaconic aciduria type 8](https://sugi.bio/atlas/disease/3-methylglutaconic-aciduria-type-8/).

**Reported phenotype names (ClinVar):** 3-methylglutaconic aciduria type 8, 3-methylglutaconic aciduria, type VIII.

## Similar variants {#similar}

Related HTRA2 variant pages (same residue, condition, or type): [HTRA2 p.Leu338del](/variant/htra2-p-leu338del), [HTRA2 p.Arg380Ter](/variant/htra2-p-arg380ter), [HTRA2 p.Arg252Gln](/variant/htra2-p-arg252gln), [HTRA2 p.Arg432Ter](/variant/htra2-p-arg432ter), [HTRA2 p.Arg49Pro](/variant/htra2-p-arg49pro), [HTRA2 p.Gly26Glu](/variant/htra2-p-gly26glu), [HTRA2 p.Ala141Ser](/variant/htra2-p-ala141ser), [HTRA2 p.Ala160=](/variant/htra2-p-ala160).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 372210). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*